title: Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model.
abstract: 22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions.
authors.affiliation: Research Institute, Shiga Medical Center, Shiga 524-8524, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Toritsuka
authors.forename: Sohei
authors.initials: S
authors.lastname: Kimoto
authors.forename: Kazue
authors.initials: K
authors.lastname: Muraki
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Landek-Salgado
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Yoshida
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yasue
authors.initials: Y
authors.lastname: Horiuchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Hiyama
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tajinda
authors.forename: Ni
authors.initials: N
authors.lastname: Keni
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Illingworth
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanigaki
mesh_terms: D058165:22q11 Deletion Syndrome / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D019718:Receptors, CXCR4
keywords: dentate gyrus; hippocampus